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Speaker: Next topic is the diabetic infected ulcer referred to in this case the ring of fire and Dr. Thomas Serena who is the vice president of America College of Hyperbaric Medicine and founder and medical director of Penn North Centers for advanced wound care from Erie, Pennsylvania is going to be discussing this. He is an expert in wound care. He has done significant research. He has published hundreds of papers and he is a Phi Beta Kappa from the graduate of William and Mary Penn State Medical School. So please welcome Dr. Serena.

Dr. Thomas Serena: Alright, so actually this is the first time that we will be presenting this and what I am going to present is a small pilot study that preceded a large clinical trial that's still ongoing. I am not going to present much from the clinical trial itself. You will have to wait thinking desert foot for that announcement but you are the first to hear officially about something that we have deemed the ring of fire. So let's start off with disclosures. Melaleuca is the company, it's a Canadian company that makes this device that I am about to show you. I don't have any relationship with them except that they pay for our research trials. So there is no other -- I don't stock or anything like that. So this is the ring of fire. You see the red around that diabetic foot ulcer. That's bacteria and in a minute I will show you how we know that's bacteria. This is a fluorescent image. It's actually not ultraviolet. It's near ultraviolet. It's a violet like and I have to tell you the inventor of this Ralph DaCosta is an optical physicist who is trained as a theoretical physicist and so over the last two years we have done nothing but talked about electromagnetic spectrum.

[02:03]

I never thought I have to talk about that after I left college. So now people ask me what my favorite color is and I say 422 nanometers, which is close to this my favorite -- Ralph's favorite color is 405 nanometers, which is what we used to see bacteria in wounds. So I am going to go over the clinical trial now, which is what are presenting. Again, the first time that anyone has heard this data so far. So we took patients in wound clinic. In fact, we used Dr. Halperin's wound clinic as part of the clinical trial and we had a number of clinics. In the pre-trial, we only used two clinics. In the subsequent trial, we have now used 15 different podiatry offices and wound care clinics and surgery offices in order to do the research. But let's go back and talk about the pre-trial, which is really what I am presenting now. We looked at wounds we thought had moderate-to-heavy bacterial burden and then we assess them clinically. Now I can tell you that research that we have done in the past and published twice show that your visual inspection of the wound is not all that good. It's accuracy is roughly in the range of about 75%. We then took a picture with the camera and we looked to see if the camera could visualize something that your clinical examination could not and then step 3 and I will go over these steps individually. We would take a picture with the camera itself. So let me start with my journey through infection in chronic wounds and it has been about 15 years that we have been trying to figure out and I will be lying if I told I figured out. The more we do -- the more research we do I think the less I know. But this is the board -- this is the chairman of the board of directors at one of our system hospital. His secretary called my front desk secretary and said Mr. Jones has an appointment Tuesday at 10 o'clock with Dr. Serena.

[04:05]

Didn't ask her, didn't ask me. She just put him in my clinic and then the secretary comes running back to say, he can't do that and I said yeah he controls my budget. He can do whatever he wants. I will see him at 10 o'clock on Tuesday and looking at that wound, what do you think infected or not infected? I said no. I mean it doesn't have surrounding cellulitis. Certainly, there is no pallo, dolor, or calor, the Latin terms and so I said no. If I hear some yeses here, you guys are smarter than me. It's clear. But turns out that when we enrolled in our clinical trials, looking at infection, did a quantitative tissue culture biopsy and it tuned out that it was positive for staph. We put a little compression and little topical antimicrobials and in six weeks it went on to heal. This is an index case. When the chairman of the board of your hospital comes to your clinic and he controls your budget for the next, that was 15 years ago, you want to know why you didn't get it right and what you could do to make yourself better. So I started looking around and Sue Gardener and I was publishing a number of papers about signs of infection and she said, well, once you will have pay attention to foul odor, wound breakdown and increasing pain. Well, that's not really very helpful Sue because all my patients smell bad and they all have open wounds and they all want opioid prescription. So this is not going to help me particularly it's the first visit that I see them. So we went back to the chairman and I said you know we did a lot of biopsies in this clinical trial. This clinical trial had 352 patients in it and the investigators -- 50 investigators across the world. When you enroll the patient you have to sign the CRF that form that you sign in the clinical trial, it says this wound is infected. And then to double check the investigators, we did a quantitative tissue culture biopsy sent to a single central lab.

[06:01]

Very, very accurate. And it turns out that of the 614 biopsies in total that we did, about 20% of the time investigators are wrong that there was increased burden and we used greater than to 10 to fifth for this. So this is really truly infection as defined by some of Martin Robson's early work. Wow, so we know that in chronic wounds that classic signs and symptoms just aren't there and so if you are inexperienced -- well, how many of you have worked in a wound clinic or see wounds in their office? I mean so have you ever seen a wound patient coming from a referral that wasn't on antibiotics? No. And I just at FDA and FDA was giving me all kinds of grief about the fact that we use too many antibiotics in the wound care world. I said just really. It's not just us. These patients -- all of these patients come into our clinics on antibiotics, that's why you are seeing these large numbers of antibiotic use. And the experience may under-treat particularly when you get below tenth to fifth margin, when the wound is just -- we used to say critical colonized but that's not a good term and we kind of change that to a period of pathogenicity, the point which the bacteria becomes pathogenic and are interfering with healing. So Gary Sibbald came up with some acronyms, NERDS and STONES. You may have heard. These are ways to look at the wound and see if you can do a better job with it and this is fantastic because he took the accuracy from 75% to 78%. So yes, we still use them but I have to tell you that we still have to do better. And this is a paper, we haven't yet published this. We are going to publish this soon. Looking at the cost and when we did a cost analysis in a large clinical trial, avoided cost just in direct dollars if you have a contaminated wound or colonized wound whether it's bacteria but it's not harming the patient, not producing proteases and then something happens in bacteria in chronic wounds.

[08:00]

At some point, it's like a light switch and they flipped the light switch and they begin producing virulence factors of proteases and those proteases are going to injure the patient that eventually will go on to spreading infection and sepsis and then amputation. So this is the camera -- sorry the name shouldn't be on there. Meant to block that out but this is the camera. The camera shines a fluorescent light at 405 nm. At 405 nm, the perforins and bacteria. Bacteria have molecules kind of like hemoglobin. Hemoglobin is also a perforin like molecule and when you shine 405 nm on a perforin, it will excite the molecule and when molecules get excited, they emit light. And this is exactly what happens here. This penetrates somewhere between 0.8 mm and up to a centimeter underneath the wound. So it's not detecting just superficial bacteria. It's going to detect bacteria that are deep within the wound. Most bacteria, strep, staph, E. coli will fluoresce red as you saw in the first picture the ring of fire. Pseudomonas has a slightly different type of molecule and if fluoresces sort of a cyano bright white color. So looking back to the trial, we took adult patients. We didn't have a whole lot of exclusion criteria for the trial. We really took anybody. One of those trials where we are going to find out how this works, anybody who walks in the door can basically be included in the example of the trial. The patient population was pretty mixed a lot of different types of wounds that particular clinic we had in this one had a heavy number of venous leg ulcers but I will tell you in the large clinical trial we are doing now with 300 patients, it's probably 50% DFU because we have a had a lot more podiatry offices in the second trial.

[10:03]

This is what it looks like. You can measure with this device as well and this is the first picture. So this is step 1. So in step 1, we took NERDS and STONES designation and we asked the investigators, is the wound infected and they would check off the signs and symptoms of infection. If you have more than three, then we say the wound is infected. It's clinically infected. That's step 1. Then we compare that clinical assessment to picture with the camera. So you darken the room because ambient light will interfere with the picture and then you look for the presence of bacteria. In this case, the venous leg ulcer and that bright on the edge there, that real white, is pseudomonas at greater than 10 to the fourth colony forming units per gram of tissue. And then a third step was we did microbiology. So it was a three-step process. We looked at physical exam, then we looked at the camera picture and then we confirmed it all with a microbiology. In this case, we used both standard culture techniques and PCR technology to identify the bacteria looking for more than 10 to the fourth bacterial species in the wound. So it was a three-step process to seek how accurate the camera was. So actually it's very accurate in seeing bacteria. The positive predictive value in this small study was 100% and I can tell you that in the subsequent clinical trials, it's not far, it's not quite this good. Remember, this is small. It's a pilot. It's 19 patients. So in the larger trial where 100s of patients, the positive predictive value is still way up in the 90s. It's extraordinarily accurate and we don't know what the negative predicted value is yet because we don't have enough -- we actually haven't enrolled patients to determine that but as soon as we do that, then we will be submitting for approval from FDA. We are very pleased to the fact that if there is bacteria in the wound, the camera sees it. It's almost ever misses it.

[12:04]

So what happens -- what effects that we have because we asked the investigator to fill out forms and what did the use of the camera do. In 47% of the patients, it identified wounds that had bacteria present when the investigator said it wasn't. That's worse than we found in our other clinical trials, almost in this trial almost 50% of the time the investigator was wrong about the amount of bacteria present in the wound. It changed treatment regimen quite a bit mostly in wound assessment and how you are going to clean and debris the wound. So in conclusion, we confirmed what we already knew. The clinical signs and symptoms of infections are not very accurate in a variety of chronic wounds that include diabetic foot ulcers, venous ulcers, pressure ulcers, etc. We found that the camera itself at least in this pilot study is very, very accurate finding bacteria greater than 10 to fourth and the fact that it has positive predictive value in the range of about 100%. So this is point of care. You can take the regular picture, measure the wound, take a second florescence picture and see if the wound has excessive amounts of bacteria. One of the first patients from the trial and what you see here is that take the first picture, I said this wound was not infected. This patient is actually on antibiotics and what you can see here is red here like it doesn't going to show up but there is red right there and this was a positive staph finding. I have been standing up in the podium, now I'm old. So I have been up here for about 20 years not this particular time but off and on and I always say, well, you debride the wound because it removes bacteria, right? Does everyone believe that? I did. Some people shaking their head because lot of people in this room are smarter than I am. People saying I don’t know if that's true or not. So I started out that way and this is little bit backward.

[14:01]

But this picture here you can see the red and I thought it was pretty superficial. So I asked the investigator -- I asked one of our podiatry officers to do a little debridement and did debridement and the red disappeared. Similarly, here this little thing here that doesn't project well. That's red in the middle of that wound and I said that looks superficial to me and when you are really good at the camera, you can tell what's deep and what superficial. And I said would you just curette out and just take that off and he did. We took another picture and it was gone. So okay may be I was right. Maybe you can, maybe debridement does remove bacteria and then we started seeing case after case after case like this one. You take a wound, you take a picture, it's red as you see here, you debride it, it still red. And I would say that the vast majority of patients that we debrided and took the picture after debridement, actually a lot of them had increased amounts of bacteria. We actually -- you took it and made the bacteria more visible and I think the reason for that is what you are seeing here in that first example that's superficial bacteria, that's bacteria that's lying on top of the wound and a lot of that what we found actually comes from the dressing itself. If there is a little bit of dressing left on the wound, it will show up red, almost every single time because actually quite a bit of bacteria in the dressings we put on wounds. So if you just scrape that off and it goes away. Oh that's good. It's not infected or being colonized but if you debride the wound and it's still there that's deeper. Remember the camera can see up to centimeter underneath the wound bed and in this case that wound [indecipherable] [00:15:37] bacterial burden. How about aseptic, so obviously a wildly positive fluorescent picture as you can see in the middle of this wound and this patient is on something -- I don't do but one of the investigators in the trial really likes it. He thought there were too much bacteria in the wounds in his clinic.

[16:00]

So he started putting everybody on Dakin's wet-to-dry for like these periods like two weeks. I don't do that. I am not promoting it but I thought this really cool because you have been using Dakin's wet-to-dry on this ulcer for two weeks and I want to take the picture of it with a florescent camera and there it is. You want to know if you Dakin's wet-to-dry is working, not so much and there is a lot of bacteria present in that wound that Dakin's had absolutely no effect on. And you get a lot of surprises at surgical wound. I don't think anybody is going to doubt that there is a lot of bacteria and this thing is floridly infected and actually cellulitic and I should have put the regular picture next to it because when you look at this with your eyes, you are going to say it's not infected at all and this is grossly I think grossly infected abdominal surgical wound. And then something else, we are learning a lot. I think we have got more questions than we do answers but this is what it looks like under a wound VAC drape under negative pressure. This is not -- the wound is up here. This is right here is what it looks like underneath your drape. There is lot of bacteria and the drape seemed to hold bacteria. Is that clinically significant? I don’t' have any clue. There are lot of things we have to find out. So the ongoing trial we are doing now with 300 patients enrolled and we are doing the same technique. We are doing clinical examination to see if the investigator and we have a lot of investigators in this trial. We have got 25 doctors working together on this trial now and they look at the wound and assess whether it's infected. We then take a picture with the camera and see whether the image looks like and then we do a quantitative tissue culture biopsy to check it and we really want to thank we have a lot of great investigators in this trial. Lot of people put a lot of time and effort. In fact, this meeting was being -- this is Gab Halperin's meeting and he and his clinic in the east LA and Dr. Jensen there have done a fabulous job in helping us. I would tell you that there is lot of infections in East LA and he has done a fabulous job in helping us to complete this trial.

[18:02]

The last thing is an advertisement and I was going to apologize, but I am not going to. So we have now 47 sites participating clinical trials. We are publishing 12 publications a year. I think it's a good reason to do that. We need more investigators that want to work with us. I think the budgets are much better now in clinical trials. The financial incentives are there. If you have an interest, let me know and we will get you involved with us. Again, we probably have two or three major clinical trials coming up that we are going to need 20 to 30 individual sites whether it's a wound clinic, private podiatry office, surgery center or anything of that nature. If you have interest in that then let me know. We love to have some more investigators working with us to find out what's going on. Particularly, as it relates to what I have just shown you here because again I think we have ended up with more questions than answers and with that I think I will stop. Thank you.

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